The aims of the present study were to evaluate the protective effects of rutin during cisplatin-induced ovarian toxicity in mice and to verify the possible involvement of the phosphatase and tension homolog (PTEN)/Forkhead box O3a (FOXO3a) pathway in the rutin actions. Mice received saline solution (control, 0.15 M, i.p.) or cisplatin (5 mg/Kg body weight, i.p.) or they were pretreated with N-acetylcysteine (positive control; 150 mg/Kg of body weight [p.o.]) or with rutin (10, 30 or 50 mg/Kg body weight, p.o.) before cisplatin (5 mg/Kg body weight, i.p.) once daily for 3 days. Next, the ovaries were harvested and destined to histological (follicular morphology and activation), immunohistochemical (cell proliferation and apoptosis) and fluorescence (reactive oxygen species [ROS], glutathione [GSH] and mitochondrial activity) analyses. Moreover, the expression of phosphorylated PTEN (p-PTEN) and FOXO3a (p-FOXO3a) were evaluated to investigate a molecular mechanism by which rutin would prevent the cisplatin-induced ovarian damage. The results showed that pretreatment with N-acetylcysteine or 10 mg/Kg rutin before cisplatin preserved the percentage of normal follicles and cell proliferation, reduced apoptosis and ROS levels and increased active mitochondria and GSH levels compared to the cisplatin treatment (P < 0.05). Cisplatin treatment increased p-PTEN and decreased p-FOXO3a expression in follicles, which was prevented by 10 mg/kg rutin. In conclusion, treatment with 10 mg/Kg rutin has the potential to protect the ovarian follicles against cisplatin-induced toxicity through its antioxidant effects and PTEN/FOXO3a pathway.

本研究的目的是评估芦丁在顺铂诱导的小鼠卵巢毒性期间的保护作用，并验证磷酸酶和张力同源物 (PTEN)/Forkhead box O3a (FOXO3a) 通路在芦丁作用中的可能参与。小鼠接受盐水溶液（对照，0.15 M，ip）或顺铂（5 mg/Kg 体重，ip）或用 N-乙酰半胱氨酸（阳性对照；150 mg/Kg 体重 [po]）或芦丁预处理（10、30 或 50 毫克/公斤体重，口服）在顺铂（5 毫克/公斤体重，腹腔注射）之前每天一次，持续 3 天。接下来，收获卵巢并进行组织学（卵泡形态和活化）、免疫组织化学（细胞增殖和凋亡）和荧光（活性氧 [ROS]、谷胱甘肽 [GSH] 和线粒体活性）分析。而且，评估磷酸化 PTEN (p-PTEN) 和 FOXO3a (p-FOXO3a) 的表达，以研究芦丁预防顺铂诱导的卵巢损伤的分子机制。结果表明，与顺铂处理相比，在顺铂前用 N-乙酰半胱氨酸或 10 mg/Kg 芦丁进行预处理可以保留正常卵泡的百分比和细胞增殖，降低细胞凋亡和 ROS 水平，增加活性线粒体和 GSH 水平（P < 0.05）。顺铂处理增加了 p-PTEN 并降低了卵泡中 p-FOXO3a 的表达，而这被 10 mg/kg 芦丁阻止。总之，用 10 mg/Kg 芦丁治疗有可能通过其抗氧化作用和 PTEN/FOXO3a 通路保护卵巢卵泡免受顺铂诱导的毒性。